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Design: ModifierEnum PATO Bindings + GOF/LOF Enum Values (Proposal A — PhenoCAM v2.5)

Date: 2026-06-26 Author: Vibhor Gupta Status: Approved for implementation Related: PhenoCAM v2.5 proposal, Issue #743

Background

PhenoCAM v2.5 is an incremental improvement strategy for the dismech pathograph model, proposed as an alternative to the full V2 schema redesign. Proposal A (this spec) is the smallest and most self-contained change: ground ModifierEnum in PATO ontology terms and add two new enum values (GAIN_OF_FUNCTION, LOSS_OF_FUNCTION) to allow structured expression of variant functional effects, which are currently buried in free-text node names.

Problem

ModifierEnum has 5 values (INCREASED, DECREASED, ABNORMAL, DYSREGULATED, ABSENT) with no meaning: bindings. This means: - The enum is not OBO-grounded — no OWL semantics, no semantic similarity reasoning - GOF/LOF must be encoded in free-text node names (e.g. "SHP2 Gain-of-Function Activation"), making them unqueryable as structured data - Curators have no enum value to reach for when a variant or activity is gain- or loss-of-function

Ontology Term Verification

All candidate PATO terms were verified via OAK (runoak -i sqlite:obo:pato) on 2026-06-26. The proposal's original PATO IDs were found to be largely hallucinated:

Enum Value Proposed ID Actual PATO term at that ID Decision
INCREASED PATO:0001998 "conspicuousness" ❌ Use PATO:0002300 "increased quality" (most general active PATO term; title: stays "Increased")
DECREASED PATO:0001997 "decreased amount" ⚠️ Use PATO:0002301 "decreased quality" (more general than "decreased amount"; title: stays "Decreased")
ABSENT PATO:0000462 "absent" ✓ Use as-is
ABNORMAL PATO:0000460 "abnormal" ✓ Use as-is
DYSREGULATED PATO:0001789 "domed" ❌ No PATO term exists — skip binding
GAIN_OF_FUNCTION PATO:0001396 "cellular quality" ❌ No suitable term — see below
LOSS_OF_FUNCTION PATO:0001561 "having extra processual parts" ❌ No suitable term — see below

GOF/LOF ontology search summary (all searched 2026-06-26):

Ontology Result
PATO All function-related terms are obsolete. No active GOF/LOF term.
GENO No GOF/LOF terms found.
GO No GOF/LOF terms found.
SO SO:0002053 / SO:0002054 exist but are variant-consequence terms, not activity modifiers. Semantic mismatch — not used.

Conclusion: GAIN_OF_FUNCTION and LOSS_OF_FUNCTION ship without meaning: bindings. This reflects a genuine gap in the biomedical ontology community — no standard activity-modifier vocabulary exists for GOF/LOF outside the variant-consequence frame.

Scope

Approach C — schema + OAK config + one exemplar KB update.

In scope

  1. Add PATO: prefix to src/dismech/schema/dismech.yaml
  2. Add meaning: bindings to 4 of the 5 existing enum values
  3. Add GAIN_OF_FUNCTION and LOSS_OF_FUNCTION as new unbound enum values
  4. Add PATO: sqlite:obo:pato to conf/oak_config.yaml
  5. Add modifier: GAIN_OF_FUNCTION to the SHP2 molecular function descriptor in kb/disorders/Noonan_Syndrome.yaml as the exemplar
  6. Run full QC (just qc) to confirm no regressions

Out of scope

  • Retroactive KB migration of existing free-text GOF/LOF node names — deferred to follow-up PR
  • Renaming pathophysiology nodes (node name is a foreign key)
  • Proposal B (kind: slot) or Proposal C (etiology block)

Changes

1. src/dismech/schema/dismech.yaml

1a. Add PATO prefix (in the prefixes: block): 

PATO: http://purl.obolibrary.org/obo/PATO_

1b. Update ModifierEnum: 

ModifierEnum:
  description: Qualifiers for direction, intensity, or pathological state of a descriptor
  permissible_values:
    INCREASED:
      title: Increased
      meaning: PATO:0002300  # increased quality
      description: Upregulated, hyperactive, elevated, or excessive
    DECREASED:
      title: Decreased
      meaning: PATO:0002301  # decreased quality
      description: Downregulated, hypoactive, reduced, or deficient
    ABNORMAL:
      title: Abnormal
      meaning: PATO:0000460  # abnormal
      description: Qualitatively abnormal (e.g., misfolding, mislocalization, malformed)
    DYSREGULATED:
      title: Dysregulated
      # No PATO term exists — verified via OAK 2026-06-26
      description: Regulation is impaired (may be increased or decreased)
    ABSENT:
      title: Absent
      meaning: PATO:0000462  # absent
      description: Not occurring or not present
    GAIN_OF_FUNCTION:
      title: Gain of function
      # No suitable ontology term found across PATO/GENO/GO/SO (verified 2026-06-26)
      # SO:0002053 exists but is a variant-consequence term, not an activity modifier
      description: Variant or activity that confers an abnormal or enhanced function
    LOSS_OF_FUNCTION:
      title: Loss of function
      # No suitable ontology term found across PATO/GENO/GO/SO (verified 2026-06-26)
      # SO:0002054 exists but is a variant-consequence term, not an activity modifier
      description: Variant or activity that reduces or abolishes normal function

2. conf/oak_config.yaml

Add entry for PATO: 

# Quality/modifier ontology
PATO: sqlite:obo:pato

3. kb/disorders/Noonan_Syndrome.yaml

In the "SHP2 Gain-of-Function Activation" node, add modifier: GAIN_OF_FUNCTION to the molecular function descriptor (one line addition):

molecular_functions:
- preferred_term: protein tyrosine phosphatase activity
  term:
    id: GO:0004725
    label: protein tyrosine phosphatase activity
  modifier: GAIN_OF_FUNCTION   # structured; previously only expressed in free-text node name

Validation

After implementation, run: 

just validate kb/disorders/Noonan_Syndrome.yaml
just validate-terms-file kb/disorders/Noonan_Syndrome.yaml
just validate-references kb/disorders/Noonan_Syndrome.yaml
just qc

No existing KB files should require changes — the new enum values are additive and the meaning: bindings on existing values are non-breaking.

Branch

feat/proposal-a-modifier-enum-pato
Worktree at ../dismech-proposal-a.

Follow-up Issues to Open

  1. Retroactive GOF/LOF migration — bulk-update free-text GOF/LOF node names across KB
  2. DYSREGULATED binding — revisit when a suitable ontology term is standardized
  3. GOF/LOF ontology binding — track SO:0002053/SO:0002054 fit if dismech modifier: semantics evolve